Zhang Hualin, Xie Ruliang, Ai-Furas Hawaa, Li Yupeng, Wu Qingxia, Li Jian, Xu Fang, Xu Tianfeng
Department of Chemistry, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai 200444, China.
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
ACS Med Chem Lett. 2022 Jan 14;13(2):278-283. doi: 10.1021/acsmedchemlett.1c00645. eCollection 2022 Feb 10.
The tertiary epidermal growth factor receptor (EGFR) C797S mutation predominates in the acquired mutational resistance in cancer patients to third-generation EGFR inhibitors. Small-molecule inhibitors targeting the EGFR C797S mutation have been developed with good efficiency. However, these compounds may still induce new EGFR mutations to evade the inhibition pathway. One EGFR protein degrader based on an allosteric inhibitor has shown some benefits of degrading the EGFR L858R/T790M/C797S triple mutant. However, the degrader of the other important triple EGFR mutation Del19/T790M/C797S has not been reported. Here we present the design and synthesis of a series of EGFR proteolysis-targeting chimeras (PROTACs) that can rapidly and potently induce EGFR degradation in Ba/F3 cells expressing the EGFR mutant. One representative compound time- and dose-dependently induced EGFR degradation with a DC of 8 nM. It also showed good antiproliferation activity (IC = 0.02 μM) against Ba/F3-EGFR cells. may serve as a lead compound to develop therapeutic agents for the treatment of resistant non-small cell lung cancer patients with EGFR C797S mutants.
第三代表皮生长因子受体（EGFR）C797S突变在癌症患者对第三代EGFR抑制剂获得性突变耐药中占主导地位。已开发出针对EGFR C797S突变的小分子抑制剂，效率良好。然而，这些化合物仍可能诱导新的EGFR突变以逃避抑制途径。一种基于变构抑制剂的EGFR蛋白降解剂已显示出降解EGFR L858R/T790M/C797S三重突变体的一些益处。然而，尚未报道另一种重要的EGFR三重突变Del19/T790M/C797S的降解剂。在此，我们展示了一系列表皮生长因子受体靶向嵌合体（PROTAC）的设计与合成，这些嵌合体能够在表达EGFR突变体的Ba/F3细胞中快速且有效地诱导EGFR降解。一种代表性化合物以时间和剂量依赖性方式诱导EGFR降解，解离常数为8 nM。它对Ba/F3-EGFR细胞也显示出良好的抗增殖活性（半数抑制浓度=0.02μM）。它可能作为先导化合物来开发治疗具有EGFR C797S突变的耐药非小细胞肺癌患者的治疗药物。
